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GLINT Report Summary

Project ID: 667510
Funded under: H2020-EU.3.1.

Periodic Reporting for period 1 - GLINT (GlucoCEST Imaging of Neoplastic Tumours)

Reporting period: 2016-01-01 to 2017-06-30

Summary of the context and overall objectives of the project

Cancer accounts for 13% of all deaths worldwide and despite recent medical improvements remains one of the most serious diseases in the world. Early detection is very important as it increases the chances of survival. Presently, cancer is detected, staged and followed-up through advanced medical imaging, e.g. computer tomography (CT), magnetic resonance imaging (MRI), and positron emission tomography (PET). As cancer is being better treated, it becomes difficult to separate the difference between treatment effects, regrowth or progression of the tumour. Currently, there is a global lack of safe, cheap, easily accessible and accurate image-based evaluation technique to detect cancer. Within the GLINT proposal, we aim to take advantage of the very high metabolism of cancer cells, which need a lot of sugar for their energy supply to be able to light it up using a new MRI method. This new technique is called ‘glucose chemical exchange saturation transfer’ (GlucoCEST), and is based on the sensitising of MRI scanners to glucose uptake, which caused tumours to appear as bright images on MR images. GlucoCEST achieves this using radio waves to magnetically label glucose in the body. This method therefore uses an injection of normal sugar and could offer a cheap, safe alternative to existing methods for detecting tumours, which require the injection of radioactive material.
The development and commercialisation of GlucoCEST MRI as an innovative in vivo new metabolic imaging technique through the GLINT consortium will:
1) enable personalised healthcare for cancer treatment by providing a cheap metabolic imaging alternative to improve patient selection
2) benefit the global cancer population by improving the diagnostic accuracy of MRI and providing early readouts of treatment efficacy, leading to improved clinical decisions and outcomes
3) reduce developmental costs of novel therapeutic molecules by providing more specific methods for patient selection and therapy monitoring.
The GlucoCEST Imaging of Neoplastic Tumours (GLINT) consortium aims to bring the combination of native glucose and a non-metabolizable glucose derivative (3-O-methyl-glucose) as a combined examination to clinical oncology practice to assess cancer glucose uptake and metabolism, thereby providing a wide-ranging new diagnostic tool for one of the most devastating diseases in the world. A major deliverable of GLINT is therefore to provide a cheap, widely available, more comprehensive, non-invasive, radiation-free complementary method to nuclear medicine techniques currently used for cancer assessment.

Work performed from the beginning of the project to the end of the period covered by the report and main results achieved so far

WP1: WP1 ensured that an appropriate project management structure and governance, reflecting the project’s needs was set up in agreement with all partners. WP1 activities covered all aspects of project monitoring, reporting, financial and contractual administration in accordance with the Commission’s rules, ensuring proper communication within the consortium and implementing the project governance’s decisions.
WP2: Bloch-McConnell simulation of GlucoCEST was established and used for glucose hydroxyl exchange rate determination at physiological condition, this information allowed to optimize the CEST/CESL presaturation in simulations. A snap-shot CEST technique was developed for Siemens 3T and 9.4T scanner and verified by protein-CEST application of in vivo scans of volunteers.
WP3: Pharmacokinetic models of the Michaelis-Menten pathway were investigated. Additionally, the CEST eval tool which allows evaluation of raw data and visualization of processed data was published on a public website and documented using YouTube tutorials. A detailed multi compartment model of the glucose pathway was developed. It will be used to understand the origin of GlucoCEST signal dynamic and simulate realistic dynamic GlucoCEST signal.
WP4: A marked 3OMG-CEST MRI contrast that was correlated with the administrated dose was obtained in various breast cancer models and by different methods of administration. 13C and 31P NMR measurements indicate the penetration of the 3OMG to the tumor with no metabolic products, respectively. Intracellular glucose measurement showed that glucose consumption was not significantly different between basal and 10 mM extracellular concentration of 3OMG.
WP5: In vitro D-Glucose provides higher CEST contrast at lower pH values, whereas 3OMG provides higher CEST contrast at neutral pH values (7.0-7.4) independent from the applied B1 saturation power level. At 7T and physiological temperature (37°C), the detection threshold is of ca. 5 mM, for a B1 level of 1 µT. In vivo studies showed that enough detectable GlucoCEST contrast is achievable after intravenous administration with a dose of 1.5 g/Kg b.w. at 7T.
WP6: A contract has been signed with Almac for the production of 3OMG for the pharmaco-toxicological studies and request of ethical approval for GLP safety pharmacology study in rodents (Irwin test) has been submitted to Italian Ministry of Health on 05 June, 2017. The in vivo study has been postponed due to a delay in 3OMG GMP-like batch delivery and will start upon the delivery.
WP7: Imaging techniques were developed jointly by UCL and MPG as well as protocol optimisation. The quantitative data analysis pipeline was established using the models developed in collaboration with OM. The first-in-man studies in head and neck carcinoma patients have been successfully carried out.
WP8: During the first period, work in WP 8 focused on the development of the initial strategies for dissemination and communication, knowledge management, and exploitation. Dissemination activities included the establishment of a visual identity and an online presence for the project, the distribution of promotional material and press releases and the presentation of GLINT at international scientific congresses and meetings.
WP9: This Work package was automatically generated by the European Commission’s online system to track the completion of the Ethics Requirements. Eighteen deliverable reports were completed to ensure that all the activities carried out in the GLINT project comply with ethical principles and relevant national, EU and international legislation.

Progress beyond the state of the art and expected potential impact (including the socio-economic impact and the wider societal implications of the project so far)

• Upon establishment and application of mathematical simulation in GlucoCEST, a new data acquisition technique called a snap-shot CEST was developed and applied to volunteers. The sequence is ready for patient measurements.
• A tool for data evaluation and visualization was published on a public website and documented using YouTube tutorials.
• A detailed multi-compartment model of the glucose pathway was developed. It will be used to understand the origin of GlucoCEST signal dynamic and simulate realistic dynamic GlucoCEST signal.
• Both native and methylated (3OMG) glucose were measured in different breast cancer models using various administration methods to assess glucose uptake and metabolism. It was found that a marked 3OMG-CEST MRI contrast was correlated with the administrated dose while no other metabolic product and no change in the metabolic profile of the tumors and the brains were observed upon the penetration of 3OMG.
• Development of imaging techniques and protocol optimisation were carried out as well as establishment of quantitative data analysis pipeline through collaborations among partners within the consortium. The first-in-man studies in head and neck carcinoma patients have been successfully performed.

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